Skip to main content

Advertisement

SpringerLink
Log in

Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

In adult tuberous sclerosis complex (TSC) patients, renal complications are the leading cause of death. Beginning in childhood, up to 80 % of patients develop renal angiomyolipoma characterized by a size-dependent risk of life-threatening bleeding. After discovery of the two causative genes, TSC1 and TSC2, and the role of mammalian target of rapamycin (mTOR) regulation in the pathogenesis of TSC, an increasing number of clinical studies evaluating mTOR inhibition in TSC patients have shown impressive results in many organ manifestations, such as brain, lung, and kidney. For renal angiomyolipoma, mTOR inhibitor treatment fundamentally changed the approach from preventive embolization or even partial nephrectomy to everolimus treatment in order to preserve kidney function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Budde K, Gaedeke J (2012) Tuberous sclerosis complex–associated angiomyolipomas: focus on mTOR inhibition. Am J Kidney Dis 59:276–283

    Article  CAS  PubMed  Google Scholar 

  2. Crino PB, Nathanson KL, Henske EP (2006) The tuberous sclerosis complex. N Engl J Med 355:1345–1356

    Article  CAS  PubMed  Google Scholar 

  3. Jozwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J (2000) Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol 15:652–659

    Article  CAS  PubMed  Google Scholar 

  4. Northrup H, Krueger DA (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243–254

    Article  PubMed  PubMed Central  Google Scholar 

  5. Krueger DA, Northrup H (2013) Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:255–265

    Article  PubMed  PubMed Central  Google Scholar 

  6. Curatolo P, Bombardieri R, Jozwiak S (2008) Tuberous sclerosis. Lancet 372:657–668

    Article  CAS  PubMed  Google Scholar 

  7. Bissler JJ, Kingswood JC (2004) Renal angiomyolipomata. Kidney Int 66:924–934

    Article  PubMed  Google Scholar 

  8. Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225:78–82

  9. Eijkemans MJ, van der Wal W, Reijnders LJ, Roes KC, van Waalwijk van Doorn-Khosrovani SB, Pelletier C, Magestro M, Zonnenberg B (2015) Long-term follow-up assessing renal angiomyolipoma treatment patterns, morbidity, and mortality: an observational study in tuberous sclerosis complex patients in the Netherlands. Am J Kidney Dis 66:638–645

    Article  PubMed  Google Scholar 

  10. Dixon BP, Hulbert JC, Bissler JJ (2011) Tuberous sclerosis complex renal disease. Nephron Exp Nephrol 118:e15–e20

    Article  PubMed  Google Scholar 

  11. Bissler J, Cappell K, Charles H, Song X, Liu Z, Prestifilippo J, Hulbert J (2015) Rates of interventional procedures in patients with tuberous sclerosis complex-related renal angiomyolipoma. Curr Med Res Opin 31:1501–1507

    Article  PubMed  Google Scholar 

  12. Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 66:792–796

    Article  CAS  PubMed  Google Scholar 

  13. O’Callaghan FJ, Noakes MJ, Martyn CN, Osborne JP (2004) An epidemiological study of renal pathology in tuberous sclerosis complex. BJU Int 94:853–857

    Article  PubMed  Google Scholar 

  14. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM, Nellist M, Gamble V, Harris PC, Sampson JR (1994) Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease–a contiguous gene syndrome. Nat Genet 8:328–332

  15. Yates JRW (2006) Tuberous sclerosis. Eur J Hum Genet 14:1065–1073

    Article  CAS  PubMed  Google Scholar 

  16. Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J, Northrup H, Au KS, Lazarus R, Domanska-Pakiela D, Kotulska K, Jozwiak S, Kwiatkowski DJ (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 121(3–4):389–400

  17. Back SJ, Andronikou S, Kilborn T, Kaplan BS, Darge K (2015) Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome. Pediatr Radiol 45:386–395

    Article  PubMed  Google Scholar 

  18. Consugar MB, Wong WC, Lundquist PA, Rossetti S, Kubly VJ, Walker DL, Rangel LI, Aspinwall R, Niaudet WP, Ozen S, David A, Velinov M, Bergstralh EJ, Bae KT, Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Sampson JR, Dawson BD, Harris PC; CRISP Consortium (2008) Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 74:1468–1479

  19. Clarke A, Hancock E, Kingswood C, Osborne JP (1999) End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant 14:988–991

    Article  CAS  PubMed  Google Scholar 

  20. Vekeman F, Magestro M, Karner P, Duh MS, Nichols T, van Waalwijk van Doorn-Khosrovani Barjesteh S, Zonnenberg BA (2015) Kidney involvement in tuberous sclerosis complex: the impact on healthcare resource use and costs. J Med Econ 18:1060–1070

    Article  PubMed  Google Scholar 

  21. Huang J, Dibble CC, Matsuzaki M, Manning BD (2008) The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28:4104–4115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dixon BP, Kingswood JC, Bissler JJ (2015) Tuberous sclerosis complex renal disease. In: Turner N, Lameire N, Goldsmith DJ, Winearls CG, Himmelfarb J, Remuzzi G (eds) Oxford textbook of clinical nephrology, 4th edn. Oxford University Press, Oxford, pp 2732–2738

    Chapter  Google Scholar 

  23. Henske EP, McCormack FX (2012) Lymphangioleiomyomatosis - a wolf in sheep’s clothing. J Clin Invest 122:3807–3816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group (2011) Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 364:1595–1606

  25. Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, Watson PC, Howe CJ, Doyle T, Pointon K, Cross JJ, Tattersfield AE, Kingswood JC, Sampson JR (2011) Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res 17:4071–4081

    Article  CAS  PubMed  Google Scholar 

  26. Taveira-DaSilva AM, Hathaway O, Stylianou M, Moss J (2011) Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus. Ann Intern Med 154:797–805, W-292-3

    Article  PubMed  PubMed Central  Google Scholar 

  27. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Whittemore VH, Thiele EA, Ford JP, Shah G, Cauwel H, Lebwohl D, Sahmoud T, Jozwiak S (2013) Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 381:125–132

    Article  CAS  PubMed  Google Scholar 

  28. Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P, Wilson KA, Byars A, Sahmoud T, Franz DN (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811

    Article  CAS  PubMed  Google Scholar 

  29. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Whittemore VH, Chen D, Sahmoud T, Shah G, Lincy J, Lebwohl D, Budde K (2013) Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 381:817–824

    Article  CAS  PubMed  Google Scholar 

  30. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, Sauter M, Nonomura N, Brakemeier S, de Vries PJ, Berkowitz N, Miao S, Segal S, Peyrard S, Budde K (2016) Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant 31:111–119

    Article  PubMed  Google Scholar 

  31. Nathan N, Wang JA, Li S, Cowen EW, Haughey M, Moss J, Darling TN (2015) Improvement of tuberous sclerosis complex (TSC) skin tumors during long-term treatment with oral sirolimus. J Am Acad Dermatol 73:802–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140–151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack FX (2001) Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 164:661e8

  34. Pirson Y (2013) Tuberous sclerosis complex-associated kidney angiomyolipoma: from contemplation to action. Nephrol Dial Transplant 28:1680–1685

    Article  PubMed  Google Scholar 

  35. Tyburczy ME, Jozwiak S, Malinowska IA, Chekaluk Y, Pugh TJ, Wu CL, Nussbaum RL, Seepo S, Dzik T, Kotulska K, Kwiatkowski DJ (2014) A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex. Hum Mol Genet 24:1836–1842

    Article  PubMed  PubMed Central  Google Scholar 

  36. Guo J, Tretiakova MS, Troxell ML, Osunkoya AO, Fadare O, Sangoi AR, Shen SS, Lopez-Beltran A, Mehra R, Heider A, Higgins JP, Harik LR, Leroy X, Gill AJ, Trpkov K, Campbell SC, Przybycin C, Magi-Galluzzi C, McKenney JK (2014) Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am J Surg Pathol 38:1457–1467

    Article  PubMed  Google Scholar 

  37. Cabrera-López C, Bullich G, Martí T, Català V, Ballarín J, Bissler JJ, Harris PC, Ars E, Torra R (2015) Insight into response to mTOR inhibition when PKD1 and TSC2 are mutated. BMC Med Genet 16:39

    Article  PubMed  PubMed Central  Google Scholar 

  38. Aguiar PV, Campistol JM, Diekmann F (2015) Safety of mTOR inhibitors in adult solid organ transplantation. Expert Opin Drug Saf

  39. Moschetta M, Reale A, Marasco C, Vacca A, Carratù MR (2014) Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations. Br J Pharmacol 171:3801–3813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Budde K, Zonnenberg BA, Frost M, Cheung W, Urva S, Brechenmacher T, Stein K, Chen D, Kingswood C, Bissler JJ (2015) Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis. Br J Clin Pharm 81:958–970

  41. Kotulska K, Borkowska J, Jozwiak S (2013) Possible prevention of tuberous sclerosis complex lesions. Pediatrics 132:e239–e242

    Article  PubMed  Google Scholar 

  42. Wiegand G, May TW, Ostertag P, Boor R, Stephani U, Franz DN (2013) Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol 17:631–638

    Article  PubMed  Google Scholar 

  43. Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA (2014) Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr 164:1195–1200

    Article  CAS  PubMed  Google Scholar 

  44. Curatolo P (2015) Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol 52:281–289

    Article  PubMed  Google Scholar 

  45. Sadowski K, Kotulska-Jóźwiak K, Jóźwiak S (2015) Role of mTOR inhibitors in epilepsy treatment. Pharmacol Rep 67:636–646

    Article  CAS  PubMed  Google Scholar 

  46. Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN (2013) Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 74:679–687

    Article  CAS  PubMed  Google Scholar 

  47. Duerr M, Glander P, Diekmann F, Dragun D, Neumayer HH, Budde K (2010) Increased incidence of angioedema with ACE inhibitors in combination with mTOR inhibitors in kidney transplant recipients. Clin J Am Soc Nephrol 5:703–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kingswood JC, Bruzzi P, Curatolo P, de Vries PJ, Fladrowski C, Hertzberg C, Jansen AC, Jozwiak S, Nabbout R, Sauter M, Touraine R, O’Callaghan F, Zonnenberg B, Crippa S, Comis S, d’Augères GB, Belousova E, Carter T, Cottin V, Dahlin M, Ferreira JC, Macaya A, Benedik MP, Sander V, Youroukos S, Castellana R, Ulker B, Feucht M (2014) TOSCA - first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet J Rare Dis 9:182

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tran LH, Zupanc ML (2015) Long-term everolimus treatment in individuals with tuberous sclerosis complex: a review of the current literature. Pediatr Neurol 53:23–30

    Article  PubMed  Google Scholar 

  50. Somers MJ, Paul E (2015) Safety considerations of mammalian target of rapamycin inhibitors in tuberous sclerosis complex and renal transplantation. J Clin Pharmacol 55:368–376

    Article  CAS  PubMed  Google Scholar 

  51. Kingswood C, Bolton P, Crawford P, Harland C, Johnson SR, Sampson JR, Shepherd C, Spink J, Demuth D, Lucchese L, Nasuti P, Gray E, Pinnegar A, Magestro M (2015) The clinical profile of tuberous sclerosis complex (TSC) in the United Kingdom: a retrospective cohort study in the Clinical Practice Research Datalink (CPRD). Eur J Paediatr Neurol

  52. Fritsche L, Budde K, Dragun D, Einecke G, Diekmann F, Neumayer HH (2004) Testosterone concentrations and sirolimus in male renal transplant patients. Am J Transplant 4:130–131

    Article  CAS  PubMed  Google Scholar 

  53. Braun M, Young J, Reiner CS, Poster D, Krauer F, Kistler AD, Kristanto P, Wang X, Liu Y, Loffing J, Andreisek G, von Eckardstein A, Senn O, Wüthrich RP, Serra AL (2012) Low-dose oral sirolimus and the risk of menstrual-cycle disturbances and ovarian cysts: analysis of the randomized controlled SUISSE ADPKD trial. PLoS One 7, e45868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Pape L, Ahlenstiel T (2014) mTOR inhibitors in pediatric kidney transplantation. Pediatr Nephrol 29:1119–1129

    Article  PubMed  Google Scholar 

  55. Ganschow R, Pape L, Sturm E, Bauer J, Melter M, Gerner P, Höcker B, Ahlenstiel T, Kemper M, Brinkert F, Sachse MM, Tönshoff B (2013) Growing experience with mTOR inhibitors in pediatric solid organ transplantation. Pediatr Transplant 17:694–706

    CAS  PubMed  Google Scholar 

  56. Kranz B, Wingen AM, Vester U, Konig J, Hoyer PF (2013) Long-term side effects of treatment with mTOR inhibitors in children after renal transplantation. Pediatr Nephrol 28:1293–1298

    Article  PubMed  Google Scholar 

  57. De Waele L, Lagae L, Mekahli D (2015) Tuberous sclerosis complex: the past and the future. Pediatr Nephrol 30:1771–1780

    Article  PubMed  Google Scholar 

  58. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, Witt O, Kohrman MH, Flamini JR, Wu JY, Curatolo P, de Vries PJ, Berkowitz N, Anak O, Niolat J, Jozwiak S (2014) Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 15:1513–1520

    Article  CAS  PubMed  Google Scholar 

  59. Franz DN, Agricola K, Mays M, Tudor C, Care MM, Holland-Bouley K, Berkowitz N, Miao S, Peyrard S, Krueger DA (2015) Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol

  60. Kotulska K, Chmielewski D, Borkowska J, Jurkiewicz E, Kuczyński D, Kmieć T, Łojszczyk B, Dunin-Wąsowicz D, Jóźwiak S (2013) Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol 17:479–485

    Article  PubMed  Google Scholar 

  61. Kingswood JC, Jozwiak S, Belousova ED, Frost MD, Kuperman RA, Bebin EM, Korf BR, Flamini JR, Kohrman MH, Sparagana SP, Wu JY, Brechenmacher T, Stein K, Berkowitz N, Bissler JJ, Franz DN (2014) The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1. Nephrol Dial Transplant 29:1203–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Curatolo P, Moavero R, de Vries PJ (2015) Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 14:733–745

    Article  PubMed  Google Scholar 

  63. Leclezio L, de Vries PJ (2015) Advances in the treatment of tuberous sclerosis complex. Curr Opin Psychiatr 28:113–120

    Google Scholar 

  64. Trelinska J, Dachowska I, Kotulska K, Fendler W, Jozwiak S, Mlynarski W (2015) Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening. Anticancer Drugs 26:437–442

    Article  CAS  PubMed  Google Scholar 

  65. Ferraresso M, Belingheri M, Ginevri F, Murer L, Dello Strologo L, Cardillo M, Parodi A, Ghirardo G, Guzzo I, Innocente A, Ghio L (2014) Three-year safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Pediatr Transplant 18:350–356

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Division of Nephrology, Charité Campus Mitte, Berlin, Germany

    S. Brakemeier, F. Bachmann & K. Budde

Authors
  1. S. Brakemeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Bachmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Budde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Brakemeier.

Ethics declarations

Conflicts of interest

SB has received honoraria and travel grants from Bristol-Myers Squibb, Novartis, Roche, Pfizer, and Alexion Astellas; FB has received honoraria and travel grants from Bristol-Myers Squibb, Novartis, and Roche; KB has received research funds and/or honoraria from Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Genentech, Hexal, Novartis, Otsuka, Pfizer, Roche, Siemens, and Veloxis Pharma.

Additional information

Answers

1. b

2. d

3. a

4. d

5. d

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brakemeier, S., Bachmann, F. & Budde, K. Treatment of renal angiomyolipoma in tuberous sclerosis complex (TSC) patients. Pediatr Nephrol 32, 1137–1144 (2017). https://doi.org/10.1007/s00467-016-3474-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-016-3474-6

Keywords

Search

Navigation